Dataset Information

Triazole-Linked Glycolipids Enhance the Susceptibility of MRSA to β-Lactam Antibiotics.

ABSTRACT: We show here that a series of triazolyl glycolipid derivatives modularly synthesized by a "click" reaction have the ability to increase the susceptibility of a drug-resistant bacterium to β-lactam antibiotics. We determine that the glycolipids can suppress the minimal inhibitory concentration of a number of ineffective β-lactams, upward of 256-fold, for methicillin-resistant Staphylococuss aureus (MRSA). The mechanism of action has been preliminarily probed and discussed.

SUBMITTER: Hu XL

PROVIDER: S-EPMC4499819 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Triazole-Linked Glycolipids Enhance the Susceptibility of MRSA to β-Lactam Antibiotics.

Hu Xi-Le XL Li Dan D Shao Lei L Dong Xiaojing X He Xiao-Peng XP Chen Guo-Rong GR Chen Daijie D

ACS medicinal chemistry letters 20150601 7

We show here that a series of triazolyl glycolipid derivatives modularly synthesized by a "click" reaction have the ability to increase the susceptibility of a drug-resistant bacterium to β-lactam antibiotics. We determine that the glycolipids can suppress the minimal inhibitory concentration of a number of ineffective β-lactams, upward of 256-fold, for methicillin-resistant Staphylococuss aureus (MRSA). The mechanism of action has been preliminarily probed and discussed. ...[more]

PMID: 26191368

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Project description:Penicillin binding protein 2a (PBP2a)-dependent resistance to β-lactam antibiotics in methicillin-resistant Staphylococcus aureus (MRSA) is regulated by the activity of the tricarboxylic acid (TCA) cycle via a poorly understood mechanism. We report that mutations in sucC and sucD, but not other TCA cycle enzymes, negatively impact β-lactam resistance without changing PBP2a expression. Increased intracellular levels of succinyl coenzyme A (succinyl-CoA) in the sucC mutant significantly perturbed lysine succinylation in the MRSA proteome. Suppressor mutations in sucA or sucB, responsible for succinyl-CoA biosynthesis, reversed sucC mutant phenotypes. The major autolysin (Atl) was the most succinylated protein in the proteome, and increased Atl succinylation in the sucC mutant was associated with loss of autolytic activity. Although PBP2a and PBP2 were also among the most succinylated proteins in the MRSA proteome, peptidoglycan architecture and cross-linking were unchanged in the sucC mutant. These data reveal that perturbation of the MRSA succinylome impacts two interconnected cell wall phenotypes, leading to repression of autolytic activity and increased susceptibility to β-lactam antibiotics. IMPORTANCE mecA-dependent methicillin resistance in MRSA is subject to regulation by numerous accessory factors involved in cell wall biosynthesis, nucleotide signaling, and central metabolism. Here, we report that mutations in the TCA cycle gene, sucC, increased susceptibility to β-lactam antibiotics and was accompanied by significant accumulation of succinyl-CoA, which in turn perturbed lysine succinylation in the proteome. Although cell wall structure and cross-linking were unchanged, significantly increased succinylation of the major autolysin Atl, which was the most succinylated protein in the proteome, was accompanied by near complete repression of autolytic activity. These findings link central metabolism and levels of succinyl-CoA to the regulation of β-lactam antibiotic resistance in MRSA through succinylome-mediated control of two interlinked cell wall phenotypes. Drug-mediated interference of the SucCD-controlled succinylome may help overcome β-lactam resistance.

Dataset Information

Triazole-Linked Glycolipids Enhance the Susceptibility of MRSA to β-Lactam Antibiotics.

Publications

Triazole-Linked Glycolipids Enhance the Susceptibility of MRSA to β-Lactam Antibiotics.

Similar Datasets

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